Project Summary/Abstract Project 1 is proposed to determine whether detection of tumor cells from liquid-based cervical cytology specimens by Pap brush (called ?PapGene? test) and/or circulating tumor DNA (ctDNA) from blood can identify early and low-volume ovarian high-grade serous carcinoma (HGSC) or its precursor lesion, serous tubal intraepithelial carcinoma (STIC). Ovarian HGSC is the most common and aggressive type of ovarian epithelial cancer. The disease is detected most often at an advanced stage due to the lack of effective screening tools. We hypothesize that ovarian cancer cells are shed from ovarian tumor or STIC into the lumen, transit through the fallopian tubes and uterus, and exit via the endocervical canal. We also hypothesize that upon invasion ovarian cancer cells and/or their DNA are shed into systemic circulation. The overall objective of Project 1 is to evaluate the clinical performance of a molecular-based cytology test (PapGene test), alone or in combination with circulating tumor DNA liquid biopsy test (ctDNA test), for early detection of HGSC. Other sample collection method such as endometrial brushing will also be evaluated. Ovarian HGSCs accounts for the vast majority of ovarian cancer deaths and its early detection has been a daunting task in the past. Development of a test that can be used for the detection of early, low-volume disease in high-risk individuals, and eventually as a screening test, would represent a significant medical advance. To develop this innovative test, we put together a multidisciplinary team and have access to unique cohorts. We propose the following specific aims: Aim 1. Define the performance characteristics of the PapGene and ctDNA tests in detecting ovarian HGSC. Aim 2. Explore the utility of PapGene and ctDNA test to detect precursor lesions and early (low- volume) ovarian HGSC in women with increased risk of ovarian cancer. Aim 3. Determine the clinical utility of the PapGene test as a screening tool for ovarian HGSC in a prospective cohort.